A Phoenix Turn For Tonix: Rising From Phase III Ashes With New PTSD Approach
Executive Summary
In an exclusive interview, Seth Lederman, CEO of New York-based Tonix Pharmaceuticals, talks about the company’s R&D rollercoaster ride and how it plans to keep its lead asset on track for approval as a treatment for post-traumatic stress disorder.
-
Tonix hopes to break new ground with a second Phase III trial in PTSD that will focus on a specific patient population defined by time since trauma.
-
As CEO, Lederman is focused on telling a new story for Tonix based on clinical data he believes will disrupt how the R&D sector and physicians view PTSD patients.
-
So what? Tonix needs to secure its new message and quickly embark on a different late-stage strategy for its lead compound in order to retain positive investor sentiment and educate the market about its fresh action plan.
It has been a bumpy journey for Tonix Pharmaceuticals Holding Corp. trying to get its lead investigational compound, TNX-102 SL, to market – despite the drug having Breakthrough Therapy status in the US for the treatment of post-traumatic stress disorder (PTSD). In an exclusive interview with In Vivo, CEO of the New York-based company, Seth Lederman, talks about Tonix’s R&D rollercoaster ride and how it hopes to keep its lead asset on track for approval.
In July 2018, Tonix was forced to stop early a Phase III trial for TNX-102 SL, also known as Tonmya (cyclobenzaprine HCl sublingual tablets). Preliminary safety data did not reveal any serious or unexpected adverse events in the trial, but benefit to patients was not significant over placebo. The HONOR study, a randomized, placebo-controlled study of up to 550 participants with PTSD at 40 US clinical sites, enrolled only active or veteran US army members.
After compelling Phase II data for Tonmya as a treatment for military PTSD, Lederman said the company thought it was in a position to intelligently design a Phase III study. However, he says that after the Phase III setback, Tonix has “learned more about how to design an excellent Phase III study.”
An Independent Data Monitoring Committee reviewed the results of the first 50% of participants (n=274) randomized in the HONOR study before recommending the trial be stopped. The primary analysis was the change from baseline in the severity of PTSD symptoms as measured by the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5).
“Psychiatry drug development is a journey, and the path certainly does not follow a straight line,” notes Lederman, who is also co-founder and chair of Tonix.
Despite success in Phase II, where a dose of 5.6mg for the oral PTSD therapy was confirmed and selected, Tonix was unable to replicate results in a large-scale study. Still, Lederman thinks the company has the information it needs to take the drug into another Phase III and to the market. “We have learned that we should study trauma closer to the time… we've had the opportunity to get feedback from a lot of experts about this.” Moving forward with Tonmya, Tonix will look at PTSD “as a condition where there are different phases.”
Lederman says there is an acceptance of this concept. “PTSD had been viewed as a single condition. So, we think that the idea of looking at it as something that has at least two phases is a step in the direction of precision medicine,” he notes. Tonix believes there are biological reasons why a treatment might have better activity in PTSD closer to the time of trauma.
What is PTSD?
Post-traumatic stress disorder is an anxiety disorder caused by very stressful, frightening or distressing events. Potential causes of PTSD include: serious road accidents, violent assaults or prolonged abuse, witnessing violent deaths, military combat, terrorist attacks and natural disasters.
Physicians use a scale to breakdown PTSD: normal stress response, acute stress response, uncomplicated PTSD, comorbid PTSD and complex PTSD. The latter is characterized as a response from repeated experiences of traumatic situations, such as severe neglect.
According to the UK’s National Health Service’s recommendations, any of the following treatment options may be considered:
-
Watchful waiting – monitoring symptoms to see whether they improve or get worse without treatment
-
Antidepressants – such as paroxetine or mirtazapine
-
Psychological therapies – such as trauma-focused cognitive behavioural therapy (CBT) or eye movement desensitisation and reprocessing (EMDR)
According to NHS resources, cases of PTSD were first documented during the First World War when soldiers developed shell shock as a result of the harrowing conditions in the trenches. Still, the condition was not officially recognized as a mental health condition until 1980, when it was included in the Diagnostic and Statistical Manual of Mental Disorders, developed by the American Psychiatric Association.
PTSD symptoms are generally grouped into four types: intrusive memories, avoidance, negative changes in thinking and mood, and changes in physical and emotional reactions.
Retrospective Analysis
Tonix presented a poster at the 2018 Military Health System Research Symposium (MHSRS) in August 2018, entitled “Effect of Time Since Trauma on Response to TNX-102 SL in Military-Related PTSD: Results of Two Double-Blind Randomized Placebo-Controlled Studies.” The presentation included results and retrospective analyses from the Phase III HONOR trial and the Phase II AtEase study.
Lederman says this was a critical opportunity for Tonix to explain its decision to halt the Phase III trial but continue clinical research for Tonmya in PTSD. “Investors were confused by our decision to stop the study, but then to announce that management was still optimistic about the drug,” he notes. “It’s challenging to be in that kind of position.”
He adds that the conference was a well-timed moment for Tonix to address questions about the future of its PTSD program. “For a large Phase III study like the HONOR trial, there is a treasure trove of data. We were simply not prepared to understand what happened in the study the morning after un-blinding.”
Based on data from two studies that included patients within 9 years of trauma and those with a longer time since trauma, Tonix thinks there is a fundamental difference in how these patients should be treated. Lederman says the general concept that PTSD evolves in different phases is very appealing. Tonix are not the first to propose this theory, but the idea that drug responsiveness may be related to these different phases of PTSD is a new concept for drug development in this space. “It will take time for that to become an accepted idea,” Lederman says. “The scientific community typically responds to new paradigms like this with both interest and scepticism.”
Phases Of PTSD
Tonix is proposing the earlier trauma population could be called “remitting PTSD” and that the longer-term population, with a longer period since trauma, might be called “persistent PTSD.”
“Those terms were in the literature before… but we think these phases that have been described by other people may correspond to a biological state that relates to responsiveness,” Lederman says. The executive adds that he thinks the company has the necessary information internally now to intelligently design another Phase III study. In more than 600 people with moderate to severe PTSD, the tolerability profile for Tonmya has been “encouraging,” Lederman says. “This is a drug that could benefit a lot of people. Everything we’ve learned about the drug indicates that it could be an approved product for PTSD.”
PTSD Pipeline
There are only two approved PTSD drugs on the US market, Vectura’s Paxil (paroxetine) and Pfizer’s Zoloft (sertraline), though other treatments are used off-label to treat the condition or to treat PTSD-related issues. The development pipeline is also very limited. Tonix’s program was the most advanced, prior to the disappointment for Tonmya in the HONOR study. As the company is continuing the program it remains at the top of the table. There are also a handful of therapy candidates in Phase II and an NMDA glutamate receptor in Phase I testing from Aptinyx Inc.
Earlier in the pipeline, there are less than 10 candidates being tested in preclinical studies as options for treating PTSD.
The two approved treatments for PTSD in the US, both serotonin reuptake inhibitors, have been on the market for many years and no longer have patent exclusivity. There has not been a novel therapy approved in the US for the treatment of PTSD since 2001. “It’s difficult to be a pioneer,” Lederman says. “We certainly have our bumps and bruises from the two trials that we’ve done… but we have never known as much about PTSD as we do now.”
Tonix’s drug, a novel low-dose formulation of cyclobenzaprine, a widely prescribed muscle relaxant with an established safety profile, targets serotonin receptor type 2a (5HT2a) and alpha-1 adrenergic receptors. The drug is designed for under-the-tongue administration, facilitating transmucosal absorption of cyclobenzaprine, which bypasses first pass liver metabolism that is necessary for orally ingested cyclobenzaprine drug products.
Tonix won a breakthrough therapy designation from the US FDA in December 2016 for the development of Tonmya in PTSD. The drug works by improving a patient’s quality of sleep in order to lessen the symptoms of PTSD. This is a different strategy for treatment than how PTSD is presently managed. The drug is not a sedative. It interacts with three receptors: the serotonin 2A receptor, which is associated with an increase in restorative slow-wave sleep; the alpha-1 adrenergic receptor, associated with reducing trauma-related nightmares and sleep disturbance; and the histamine-1 receptor, associated with the reversal of stress-induced increases in rapid eye movement (REM) sleep. The drug is a long-term medicine that does not start impacting sleep until approximately two weeks after patients start taking it.
Tonix originally tested TNX-102 SL as a treatment for fibromyalgia, where Phase III studies were also initiated. However, this program was suspended in 2016 after the AFFIRM trial failed to meet its primary endpoint. Tonix said at the time that it would end activities in fibromyalgia to concentrate its resources in PTSD – adding pressure to Tonix’s need for success in this indication. When the company started to investigate its compound in PTSD, around 2014, the number of ongoing studies for new therapies was very limited. “When we started, it was almost like a new field.” (Also see "Tonix Drops Fibromyalgia, Will Pursue PTSD Claim With Cyclobenzaprine Formulation" - Pink Sheet, 6 Sep, 2016.)
| Drug Name | Lead Company | Current Phase | Target |
| NYX-783 | Aptinyx | I | NMDA Glutamate Receptor |
| BNC210 | Bionomics | II | Nicotinic Acetylcholine Receptor |
| Midomafetamine | Multidisciplinary Association for Psychedelic Studies | II | Trace Amine Associated Receptor 1 |
| PRX-3140 | Nanotherapeutics | II | Serotonin 5-HT4 receptor |
| Rexulti | Otsuka | II | Dopamine 2 Receptor |
| SLS-002 | Seelos Therapeutics | II | NMDA Glutamate Receptor |
| PF-04457845 | SpringWorks Therapeutics | II | Fatty Acid Amide Hydrolase |
| Tonmya (TNX-102 SL) | Tonix Pharmaceuticals | III | Alpha-1 Adrenergic Receptor/ Serotonin 5-HT2A receptor |
| Paxil | Vectura Group | Approved (Generic Competition) | Serotonin Reuptake |
| Zoloft | Pfizer | Approved (Generic Competition) | Serotonin Reuptake |
Next Steps For Tonmya
Tonix is meeting with the FDA this month to discuss the next steps for its PTSD program. In its Phase II trial, the company recruited veterans, reservists and active duty members of the US military who were relatively close to trauma. Lederman thinks it is noteworthy that this study took place within nine years of a period of time when the US had millions of active duty personnel deployed in Iraq and Afghanistan. The protocol devised for the Phase II study was military-related trauma that occurred in 2001 and later. The concept was to capture the generation of post-9/11 military trauma.
In the Phase II AtEase study, the median time since trauma was 6 years. In the Phase III HONOR trial the median time since trauma was 9.5 years. In the larger study, there was also a significant number of people who had experienced trauma between 14 and 17 years ago. “There were no protocol violations, it was just that we didn’t know that this would be an important parameter,” Lederman says.
In the next planned Phase III for Tonmya, Tonix does not believe it will be possible, in the US only, to recruit a population of military-related PTSD that is less than 9 years since trauma. “We are likely going to propose to the FDA a trial that will be more all-comers. Meaning that we will certainly look for military PTSD because of our commitment to that group of people, but we hope to look at the civilian population as well in that study.”
Lederman notes that the civilian population with PTSD in the US is around four-times the size of the military PTSD population. He adds that Tonix has no reason to think the civilian population will be harder to treat. “In fact, as a general concept, existing studies show that civilian PTSD is more responsive to treatment.”
Tonix is also investigating Tonmya in Alzheimer’s disease, but research is at a much earlier stage for this indication than the PTSD program. The company believes its drug has potential as a treatment for Alzheimer’s agitation, however clinical studies in this area have been put on hold for the time being until Tonix can get the PTSD program back on track. Before the failure of the HONOR trial, Tonix had been planning a Phase II for Tonmya in Alzheimer’s agitation.
Fund Raising
Prior to the Phase III setback, Tonix had been seeking potential partners for the drug. The company has not given up on this strategy, “It’s not uncommon for partners to have a different view on a program than, for example, investors,” Lederman says. “At least some potential partners understand that our program has never been more valuable… we have more human exposure, more data and we are essentially closer to approval than before we got these data.” Psychiatry as a development area has historically been reliant on companies that have a long-term view, patience and the ability to learn from trial-to-trial.
If the company is unable to secure a partner for the next Phase III study of Tonmya, Lederman is optimistic Tonix can afford to continue alone. Once Tonix has a clear direction from the FDA, it will have more information on the risk, reward and cost of a new Phase III. “An all comers-style will make the trial faster and less expensive to enrol,” Tonix’s CEO adds. He notes that it was challenging to study only military PTSD and enroll enough patients into the previous trials because of the culture of stoicism in the veterans, reservists and active duty people. Tonix had to invest in education and training to figure out the best way to engage and recruit military members. “From what we understand of civilian PTSD, the challenges of enrolling patients will still be present, but they will not be as challenging as military PTSD.”
In September 2018, the company filed an S-1 with the SEC to raise up to $12 million in a secondary public offering. Pricing terms had not been disclosed at the time of publishing. The company intends to use the net proceeds, together with existing cash, to fund the new Phase III study using a modified design.
Lederman is hopeful that Tonix will be able to lead the emerging wave of PTSD drug development and be the first to get an approved product to market in the US in almost two decades.